N-aroyl alanine amides



' methoxy-benzoic Patented Feb. 7, 1950 N-AROYL ALANINE AMIDES HenryMartin and Hans Gysin, Basel, Switzerland, assignors zerland, aSwiss-firm to J. R. Geigy A. G., Basel, Swit- No Drawing. ApplicationNovember 25, 1947, Se-

rial No. 788,096. In Switzerland December 18,

4 Claims.

1 This patent application is a continuation-inart application to ourco-pending patent applization Ser. No. 551,636 filed on August 28, 1944(issued as U. S. Patent No. 2,447,587, on August 24; 1948) which isitself a continuation-in-part application to our patent application Ser.No. 510,402 filed on November 15, 1943 (now abandoned).

The present invention is concerned with compounds of the generalformula:

lower alkylz lower a1kyl1-CHC O-N lower alkyla lower alkylr-JL- C Owherein lower alkyli means a member of the group consisting of methyland ethyl radicals, lower alkylsz, 3 and 4 each mean an alkyl group withat most three carbon atoms, and R1 and R2 each mean a member of thegroup consisting of hydrogen, alliyl, alkoxy and halogen, the alkyl andalkoxy groups containing at most three carbon atoms.

Compounds of the above defined formula can be prepared in various ways.A preferred method consists in acylating N-monoalliylatedaminocarboxylic acid dialkylamides with carboxylic acids of the benzeneseries. Acylation can be carried out by the usual methods, especially bythe action of the corresponding carboxylic acid chloride on theN-monoalkylated aminocarboxylic acid dialkylamides.

The following may be named as examples of carboxylic acids of thebenzene series which can be used for acylation: benzoic acid, o-, mandpmethyl-benzoic acids, 2:4-, 215-, 2:6-, 3:4- and 3:5-dimethyl-benzoicacids, p-ethyl-benzoic acid, 4-methyl-2propyl-benzoic acid, mandpmethoxy-benzoic acids, 2:4-, 3:4- and 3:5-diacids,3-methyl-4-methoxybenzoic acid, o-ethoxy-benzoic acid,p-isopropoxy-benzoic acid, o-, mand p-chloro-benzoic acids,3:4-dichloro-benzoic acid, p-fluoro-benzoic acid, o-;, mandp-bromo-benzoic acids, Z-bromo- 4-meth-oxy-benzoic acid and so on.

As N-alkylated aminocarboxylic acid amides the following may be named byway of examples: aethylamino propionic acid dimethylamide, aethylaminopropionic acid diethylamide, ozmethylamino butyric acid dimethylamide,ozethylamino-butryric acid-dimethylamide, oc-PIO-plyamino-butryric--acid-dimethylamide, u-ethylamino-butyric acid-(methyl ethyl-amide), amethylamino butyric acid (methyl propylamide,a-ethylamino-propionic acid-diallylamide and so on.

The following examples serve to illustrate the present invention,without of course limiting it to them. In these examples parts arealways partsby weight and degrees are degrees centigrade.

EXAMPLE 1 CH3--CH-C ON(CH3)1 o H3-C TIT-1L0 O-QCH:

144 parts of u-ethylamino-propionic acid dimethylamide are dissolved in500 parts of dry ether and 84 parts of 3:4-dimethyl-benzoylchloride areadded dropwise while cooling and stirring. After all the acid chloridehas been added the reaction mixture'is stirred for a further two hoursat room temperature and the a-ethylamino-propionic acid-dimethylamide-hydrochloride removed by filtration under suction. The solvent isthen distilled ed and water is added to the residue, followed bysaturation with potassium hydroxide. The N- (3:4-dimethyl-benzoyl) onethylamino propionic acid dimethylamide which separates is taken up inbenzene and dried over potassium hydroxide. After the benzene has beendistilled off the new compound is rectified by distillation in a highvacuum. It boils at 1'70- 173 at a pres-sure of 0.07 mm., is moderatelysoluble in water and readily soluble in organic solvents.

If 84 parts of 3.4-dimethyl-benzoyl chloride in the above example arereplaced by 88 parts of l-chlorobenzoyl chloride, then the product is N(ozchloro-benzoyD- a -ethylamino-propionic acid-dimethylamide, boilingat l68-l70 at 0.1 mm. pressure, which is sparingly soluble in I waterbut readily soluble in organic solvents.

Example 2 01134311? CHG O'N(CH;4);

30 parts of potassium carbonate are added to a solution of 29 parts ofu-methylamino-butyric acid-dimethylamide in 200 parts of dry'acetone.This is followed by the dropwise addition of 40 parts of veratric acidchloride. When .all the latnas esse s aeq-d r v lter has been added, themixture is kept boiling overnight. The acetone is then distilled oil andwater added to the residue followed by saturation with potassiumhydroxide. The upper layer is then taken ,up in benzene. After dryingover potassium hydroxide, the solvent is distilled off and the remainingN-veratroyl-m-methylaminobutyric acid-dimethylamide is purified bydistillation in' a high vacuum. The new substance is a very viscous oilwith a boiling point of 192-193 at 0.2 mm. pressure. It is easilysoluble in water and organic solvents.

In the following table are listed further compounds which may beprepared as described in the above examples: l0

Solubility in water (w) Solubility in ether (e) CHrOHC ON(CH3);l63165/0.06 w: moderately e' readily CzHr-NC o-O CHrCH-C ON(CH):l94-195/0.05 w: readily e: readily CHrCHz-N-C O-OO CH:

CHq-CHC ON(CH;): 167l68/0.08 w: slightly e: readily ClH5-"N*-C o-O 733B: CH3CHC 0N(CH:)2 2l5-217/0.15 w: miscible e: miscible C1H;N-C o-QoCH5 CH;CH-C ON(C2H5)2 19s-200/0.1 w: moderately e: readily ClHr-NC oackoCH! CHy-GHz-CH-C omen, 212-215/0.05 w: moderately e: readily CHz-CHg-N-C00-0 CH;

CHrOHz-CH-C ON(CH3)1 187190/0.05 w: slightly e: readily CHe-CH-N-C 000OH:

0113-0132-0114: 0N(0H, 220221/0.05 w; readily I e: readily cm-cm-N-c 0 0CH:

CH: CHr-CHg-CH-C ON(C2H5)2 203-20s/o.os w: slightly I e: readily GHr-N-O0 -0 CH3 OHz-OHg-O 11-0 0N(C1H5)g 2092l0/0.12 w: slightly I e: readilyCHa-C Hr-N-O 0 0 CH3 The compounds of the present invention are mostlyviscous to very viscous liquids. They 65 have valuable therapeuticproperties and in particular they possess analeptic activity.

What we claim is:

1. The acylated aliphatic aminocarboxylic acid dialkylamide of theformula 70 CHr-OHr-OH-C ON(CH:):

CH;N-O 0 OCH;

which is a colourless liquid with a boiling point of 168-170 at 0.1 mm.mercury pressure.

3. The acylated aliphatic aminocarboxylic acid dialkylamide of theformula.

(BCH

which is a colourless liquid with a boiling point of 203-205 at 0.08 mm.mercury pressure.

4. A compound of the formula R1CHCON(R3)2 R2NC O-Rl I wherein R1 and R2each represents a member selected from the group consisting of methyland ethyl, R1 and R2 containing together at least three carbon atoms, R3represents a member selected from the group consisting of a methyl andethyl, and R4 represents a member selected from the group consisting ofa phenyl-, ch1orophenyl-, methylphenyl, and methoxyphenyl-radicals.

HENRY MARTIN. HANS GYSIN.

REFERENCES CITED The following references are of record in the file ofthis patent:

Karrer,He1v.Chim. Aota, vol. 8 (1925) p. 217.

Braum, Ber. deut. chem, vol. 60 (1927), p. 353.

Sedgwick, "Organic Chemistry of Nitrogen, (1937), page 138.

Chemical Abstracts, vol. 35, page 2593 (1941), (Abstract of Lettre et211., Z. Physiol Chem, vol. 266 (1940), pages 31 to 36).

1. THE ACYLATED ALIPHATIC AMINOCARBOXYLIC ACID DIALKYLAMIDE OF THEFORMULA